Figure 2.

TPO signaling pathway. In unstimulated cells (A), Mpl (in yellow) exists as a monomer, and signaling molecules, such as JAK2 and STATs, are inactive. Upon TPO binding (B), Mpl dimerizes. This conformational change results in phosphorylation of its associated JAK2 molecules, which leads to phosphorylation of Mpl and activation of downstream signaling pathways, including STATs, the MAPK pathway and the PI3K pathway. JAK2 can phosphorylate STAT3 and STAT5 in response to TPO signaling, which results in their dimerization and translocation to the nucleus. There transcription is initiated, and the integration of these pathways leads to the downstream effect of TPO. STATs also induce transcription of SOCS proteins, which are generally not expressed, resulting in negative feedback and downregulation of JAK2 and Mpl activation.